Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.

com

Copy-number variation

ORIGINAL ARTICLE

A 600 kb deletion syndrome at 16p11.2 leads to

energy imbalance and neuropsychiatric disorders
Flore Zufferey,1 Elliott H Sherr,2 Noam D Beckmann,1 Ellen Hanson,3 Anne M Maillard,1
Loyse Hippolyte,1 Aurélien Macé,4,5 Carina Ferrari,6 Zoltán Kutalik,4,5 Joris Andrieux,7
Elizabeth Aylward,8 Mandy Barker,9 Raphael Bernier,10 Sonia Bouquillon,7
Philippe Conus,6 Bruno Delobel,11 W Andrew Faucett,12 Robin P Goin-Kochel,13
Ellen Grant,14 Louise Harewood,15 Jill V Hunter,16 Sébastien Lebon,17
David H Ledbetter,12 Christa Lese Martin,18 Katrin Männik,15 Danielle Martinet,1
Pratik Mukherjee,19 Melissa B Ramocki,20 Sarah J Spence,21 Kyle J Steinman,22
Jennifer Tjernagel,23 John E Spiro,23 Alexandre Reymond,15 Jacques S Beckmann,1,4
Wendy K Chung,24 Sébastien Jacquemont,1 on behalf of the Simons VIP Consortium,*
on behalf of the 16p11.2 European Consortium*

▸ Additional supplementary ABSTRACT recurrent interstitial deletion, of a ∼600 kb region

files are published online only.
To view these files please visit
the journal online (http://dx.doi.
org/10.1136/jmedgenet-2012-
101203).
For numbered affiliations see
end of article
Correspondence to Dr Wendy
Chung, Division of Molecular
Genetics, Department of
Pediatrics, Columbia University,
Russ Berrie Pavilion, 1150
St Nicholas Avenue, Rm 620,
New York, NY 10032, USA,
wkc15@columbia.edu; Jacques
S Beckmann, Service de
Génétique Médicale, CHUV, Ave
Pierrre Decker, 2,
1011 Lausanne, Switzerland,
jacques.beckmann@unil.ch;
Alexandre Reymond, Center for
Integrative Genomics, University
of Lausanne, Le Génopode, 1015
Lausanne, Switzerland,
alexandre.reymond@unil.ch;
Sébastien Jacquemont, Service
de Génétique Médicale, CHUV,
Ave Pierrre Decker, 2,
1011 Lausanne, Switzerland,
sebastien.jacquemont@chuv.ch
FZ, EHS, NDB, EH: equally
contributing first authors.
AR, JSB, WKC, SJ: equally
contributing senior authors.
Received 31 July 2012
Revised 22 August 2012
Accepted 24 August 2012
This paper is freely available
online under the BMJ Journals
unlocked scheme, see http://
jmg.bmj.com/site/about/
unlocked.xhtml
Background The recurrent ∼600 kb 16p11.2 BP4-BP5
deletion is among the most frequent known genetic
aetiologies of autism spectrum disorder (ASD) and
related neurodevelopmental disorders.
Objective To define the medical, neuropsychological,
and behavioural phenotypes in carriers of this deletion.
Methods We collected clinical data on 285 deletion
carriers and performed detailed evaluations on 72
carriers and 68 intrafamilial non-carrier controls.
Results When compared to intrafamilial controls, full
scale intelligence quotient (FSIQ) is two standard
deviations lower in carriers, and there is no difference
between carriers referred for neurodevelopmental
disorders and carriers identified through cascade family
testing. Verbal IQ (mean 74) is lower than non-verbal IQ
(mean 83) and a majority of carriers require speech
therapy. Over 80% of individuals exhibit psychiatric
disorders including ASD, which is present in 15% of the
paediatric carriers. Increase in head circumference (HC)
during infancy is similar to the HC and brain growth
patterns observed in idiopathic ASD. Obesity, a major
comorbidity present in 50% of the carriers by the age of
7 years, does not correlate with FSIQ or any behavioural
trait. Seizures are present in 24% of carriers and occur
independently of other symptoms. Malformations are
infrequently found, confirming only a few of the
previously reported associations.
Conclusions The 16p11.2 deletion impacts in a
quantitative and independent manner FSIQ, behaviour and
body mass index, possibly through direct influences on
neural circuitry. Although non-specific, these features are
clinically significant and reproducible. Lastly, this study
demonstrates the necessity of studying large patient
cohorts ascertained through multiple methods to
characterise the clinical consequences of rare variants
involved in common diseases.
INTRODUCTION
The 16p11.2 locus (figure 1) encompasses several
distinct genomic structural variants, including a
containing 29 genes.1 This deletion defined by
breakpoints 4 and 5 (BP4-BP5) has a population
prevalence of approximately 1/2000,2 and reaches
0.5% in autism spectrum disorders (ASD).3–7 It is
one of the most frequent known single locus aeti-
ologies of neurodevelopmental disorders and ASD.8
We and others have demonstrated that this dele-
tion predisposes to a highly penetrant form of
obesity with a 43-fold increased risk of developing
morbid obesity.1 9 Increased head circumference
(HC) has also been associated with the deletion.2 10
A mirror phenotype is observed in carriers of the
reciprocal duplication who present a high risk of
being underweight and microcephalic.2 10
The diversity of published clinical features,10–14
together with the report of asymptomatic (but not
fully evaluated) transmitting parents,10 15 16 demon-
strated the need to assess systematically the impact
of the deletion on neurocognitive development and
behaviour.15 To identify the essential clinical traits
accurately and assist with genetic counselling,
through a collaborative effort we have collected the
largest dataset of 16p11.2 BP4-BP5 ∼600 kb deletion
carriers. It combines deletion carriers from both the
16p11.2 European and Simons Variation in
Individuals Project (Simons VIP) consortia (n=116
and n=52, respectively). We present in this report
the natural history, frequency, and range of pheno-
types of this rearrangement. We demonstrate that
the 16p11.2 deletion consistently impacts cognitive
functioning, behaviour, growth, and body mass
index (BMI).
PATIENTS AND METHODS
Patients
This study was reviewed and approved by the insti-
tutional review board of each site conducting the
study. Signed consents were obtained from partici-
pants who underwent full assessments. For the
data collected through questionnaires, information
was gathered retrospectively and anonymously by

660 J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203

 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com

Copy-number variation

Figure 1 The 16p11.2 locus. Highly homologous blocks of low copy repeats (LCRs) may act as substrates for non-allelic homologous
recombination, predisposing to genomic disorders.48 Five LCRs have been defined as mediators of recurrent and clinically relevant imbalances within
the 16p11.2 chromosomal band. To clarify the terminology, we propose to number these ‘recombination hotspots’ from telomere to centromere as
breakpoints BP1 to BP5. The current study describes only features associated with the proximal 600 kb recurrent deletion, delineated by BP4 and
BP5 at genome sequence coordinates 29.5 and 30.1 Mb, respectively. Distal BP2-BP3 and BP1-BP3 mediated rearrangements, of respectively 220
and 550 kb, containing the SH2B1 gene, have also been reported in individuals with early onset obesity and variable degrees of developmental
delay.49 Several recurrent rearrangements overlap the proximal BP4-BP5 region studied here including the 1.7 Mb deletions and duplications from
BP1 to BP59 which should be considered as distinct entities. (A) Rearrangements are schematically pinpointed with reddish bars while grey bars
and striated blocks indicate intervals of recurrent polymorphisms reported in the Database of Genomic Variants (http://projects.tcag.ca/variation) and
common sequence stretches, respectively. (B) Genes encompassed by the genomic region between BP4 and BP5 are shown. All genomic positions
are given according to the human genome build hg18/NCBI 36.

physicians who had ordered comparative genomic hybridisation
(CGH) analyses performed for patient care purposes only.17
Consequently, research based informed consent was not required
by the institutional review board of the University of Lausanne
which granted an exemption for this part of the data collection.
Carriers were ascertained through several cohorts (table 1).
Details on ascertainment and data collection for the partici-
pants have been previously published.2 18 All participants in
the Simons VIP cohort were mapped using whole genome
oligonucleotide arrays, and were found to have the common,

Table 1 Ascertainment of deletion carriers

Inheritance
De novo/inherited
Cohorts† Mean age (y) Carriers M F Sex ratio p Value (mother:father:unknown) Patients screened
** −3
Europe† Probands 10.7 85 56 28 1.49×10 25/28 (17 : 10 : 1) 30635**
Carriers siblings 13.9 9 6 3 0.25 NA
Transmitting parents 37.4 22 8 13 0.19 NA
Simons VIP Probands 8.2 45*** 26 19 0.19 27/7 (2 : 3:2) 15749***
Carriers siblings 8.7 4 0 4 0.62 NA
Transmitting parents 42.7 3 2 1 – NA
Literature DD/ID§ 9.8 84 56 28 1.49×10−3 38/15 (8 : 7:0) NA
General population‡ 45.1 18* 8 10 0.41 NA 58635*
Obesity‡ 26.5 15 4 11 0.59 2/3 (3 : 0:0) 2579
Carriers TOTAL – 285 166 117 2.12×10−3 92/53(30 : 20) 107598
†Distribution of clinical indications for referral is detailed in the previous publication.2
‡Only anthropometric data were available and previously published.1 2
§Cases (including 7 relatives) reviewed from the literature.4 5 7 10 11 13–16 19–23 The copy number variant detection methods used in the literature are: 19K bacterial artificial chromosome
(BAC) microarray,4 Affymetrix 500K,5 Affymetrix 5.0,7 44K and 105K Agilent,10 44K and 105K Agilent,11 105K Agilent,14 Affymetrix 500K, Affymetrix 6.0, Illumina HumanHap300 BeadChip,
38K BAC microarray (Swegene), 44K, 105K and 244K Agilent,15 Affymetrix 500K, Affymetrix 6.0, and Illumina 1M,16 BAC microarray,19 Affymetrix 6.0,20 Agilent 105K,21 NimbleGen HD2,
Affymetrix 6.0, Affymetrix 500K or ROMA 85K,22 244K Agilent or Affymetrix 6.0.23
Data were available on 18/25*, 85/113** and 45/67*** deletion carriers.
Due to missing data, there may be differences between the total number of cases and the sum of cases in the various columns. Statistically significant values are in bold.
DD/ID, developmental disorders/intellectual disability; NA, non-available or not applicable; Simons VIP, Simons Variation in Individuals Project.

J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203 661

 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com
Copy-number variation
recurrent 16p11.2 BP4-BP5 deletion. Data for 96 carriers (76
probands and 20 relatives) from the European consortium were
obtained by completion of a questionnaire by referring clini-
cians. Fifty-four probands and 18 relatives (n=72) were exten-
sively evaluated on site by investigators of one of the consortia.
Data on 117 deletion carriers ascertained for developmental dis-
orders/intellectual disability (DD/ID) (n=84) , obesity (n=15)
and from the general population cohorts (n=18), were collected
from our previously published studies, as well as from the lit-
erature.1 2 4 5 7 10 11 13–16 19–23
In the Simons VIP cohort, four patients were excluded based
on the presence of additional pathological copy number var-
iants (CNV), other genetic diagnoses, birth asphyxia, fetal
alcohol syndrome, and/or prematurity <30 weeks. In the
European series, known additional variants (three carriers with
a CNV >500 kb and a pair of twins with an FGFR3 mutation)
did not represent an exclusion criterion. The inclusion or exclu-
sion of these five carriers did not have an impact on any results
(supplementary table S1). They were included in the final ana-
lysis because of the arbitrariness of this filtering that only takes
into account visible rearrangements and/or known point muta-
tions. We have to assume that many additional mutational
events not detectable by CGH array may be present in this
dataset.
In the VIP cohort, ethnicity was 75% Caucasian, 5.8%
African American, 1.9% Native American, 7.7% other (mixed
ancestry), 9.6% unknown (adopted). For the 72 patients evalu-
ated on site in the European cohort, all carriers were of
European descent.
All available data on patients ascertained for DD/ID from
the 16p11.2 European cohort, Simons VIP and the literature
(n=285) were pooled for statistical analysis. Due to missing
data for some phenotypes, the denominator changes, which is
specified throughout the text. Data collected through question-
naires or by direct assessment are presented separately in sup-
plementary tables S2 and S3. The 33 deletion carriers from the
general population and obesity cohorts, for which only
anthropometric data were available, are used in the analysis of
growth parameters alone. Full scale intelligence quotient
(FSIQ) was assessed in 68 intrafamilial controls. The Simons
Simplex Collection (SSC)24 was used as an ASD reference popu-
lation to investigate the effect of obesity on the frequency of
macrocephaly in patients with a neurodevelopmental disorder.
Cognitive functioning, psychiatric and behavioural assessment
Overall cognitive functioning was assessed using either the
Mullen Scales of Early Learning, the Differential Ability
Scales—Second Edition (Early Years and School Age, DAS-II),
the Wechsler Intelligence Scales (WPPSI-III; WISC-IV; WAIS-III)
or the Wechsler Abbreviated Scales of Intelligence, depending
on the age and ability level of the individual.25 Vineland
Adaptive Behaviour Scales (VABS)26 were used to measure
adaptive skills in daily life. Intellectual disability (ID) was diag-
nosed as having an FSIQ of 70 or below on a standardised IQ
test as well as concurrent deficits in adaptive functioning as
defined by the Diagnostic and Statistical Manual of Mental
Disorders, 4th edition, text revision (DSM-IV-TR) criteria.27
Different standardised neuropsychological measures were
used to assess global cognitive functioning of carriers in the lit-
erature.5 11 15 16 23 For the purpose of this study, throughout
the text we use the term FSIQ to refer to normalised cognitive
levels (general population mean=100; standard deviation
(SD)=15). ASD was diagnosed by experienced, research-reliable
clinicians using the Autism Diagnostic Interview—Revised
662
(ADI-R)28 and the Autism Diagnostic Observation Schedule
(ADOS).29 The Diagnostic Interview for Genetic Studies
(DIGS)30 was performed for adults, while children’s behavioural
and emotional problems were assessed with parent report ques-
tionnaires.31–33 Additional DSM-IV-TR diagnoses were made
by licensed psychologists and psychiatrists using history, parent
report and in-person interview. For all aforementioned evalua-
tions, the clinicians were not blinded to the genetic status of
the participants.
Statistical analyses
To prevent bias due to intrafamilial correlations, deletion-
carrying relatives of probands were excluded as required to
avoid including more than one member of the same family in a
single analysis. Obesity and morbid obesity in adults are
defined throughout the study as BMI ≥30 and 40 kg/m2,
respectively. Z scores were computed for all data using gender,
age, and geographically matched reference populations as previ-
ously described.1 Obesity in children and macrocephaly were
defined as BMI and HC Z score ≥2, respectively.
One-tailed Fisher ’s exact test was used to compare frequen-
cies of the deletion in patients and controls. Two-tailed
Student’s t test was performed to assess whether BMI,
height, weight, and HC Z scores of deletion carriers were dif-
ferent from zero (general population mean). Correlation
between these features and FSIQ were examined using
Spearman correlation. The binomial test was performed to
test for gender bias.
A linear model was applied to correct HC Z scores for BMI,
age, and gender effects, using Matlab function regress. A two-
tailed Student t test was performed to test the residual effects
being different from zero. Linear mixed effect model was used
to analyse the longitudinal and cross-sectional data and prop-
erly handle autocorrelations. Model fitting was performed to
obtain the mean Z score and the corresponding p value for a
given time window. The calculations were done using the lme
function from the R package nlme.
For each of the W age windows the mean Z scores were com-
puted for each of the P patients resulting in a W×P matrix.
Since W tests were carried out, we applied a multiple testing
correction that takes into account the correlation structure of
the test statistics. As a first step, the effective number of tests
(Weff ) was derived based on the Pearson’s correlation matrix of
the W×P dataset.34 We then applied Bonferroni correction of
the linear mixed effect model p values, but using Weff instead
of W tests to correct for multiple testing.
Breakpoint mapping with short arm of chromosome 16 custom
array CGH
To confirm 16p11.2 deletions and ensure that the breakpoints
are within the BP4 and BP5 low copy repeats (figure 1), we
hybridised Cy3-labelled DNA of the European patients to
custom made Nimblegen arrays. These arrays contained 71 000
probes spread across the short arm of chromosome 16 from
22.0 to 32.7 Mb (at a median space of 45 bp between 27.5 and
31.0 Mb) and 1000 control probes situated in invariable region
of the X chromosome.2 Cy5-labelled DNA from the GM12042
CEPH (Centre d’Etude du Polymorphisme Humain) cell line was
invariably used as reference. DNA labelling, hybridisation and
washing were performed according to Nimblegen protocols.
Scanning was performed using an Agilent G2565BA Microarray
Scanner. Image processing, quality control, and data extraction
were performed using the Nimblescan software V.2.5.
J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203
 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com

Copy-number variation

Figure 2 Distribution of full scale intelligence quotient (FSIQ) and body mass index (BMI) in deletion carriers.(A) Distribution of FSIQ of 16p11.2
BP4-BP5 deletion carriers (grey bars), intrafamilial non-carrier relatives (control, blue bars) and general population (blue bell curve). The red dashed
vertical line represents the FSIQ threshold (70) for intellectual disability (ID). FSIQ is on average 32 points lower in carriers (n=71; mean=76.1;
SD=16.4) when compared to their relatives who did not carry the deletion (n=68; mean=108.3; SD=10.9). SD in carriers is similar to that of the
reference population (mean=100; SD=15). Bin size was calculated to obtain 10 equal sized bins. (B) Cross-sectional distribution of BMI in carriers
(circles: female; open squares: male). BMI progressively increases throughout childhood and adulthood. 70% of the adult carriers are obese (BMI
≥30). The dashed lines represent the 3rd and 97th Center for Disease Control and Prevention (CDC) centile, while the dotted lines pinpoint the
thresholds for underweight (BMI=18.5), obesity (30), and morbid obesity (40).

RESULTS (relatives who carry the deletion) (table 2, supplementary table

The extent of the 16p11.2 rearrangements was assessed by aCGH
through standard medical diagnostic procedures and confirmed
by a high density custom made array as published (see
Methods).2 35 Only carriers of the ∼600 kb 16p11.2 BP4-BP5
deletion were considered for further phenotyping; we gathered
clinical information on 285 such carriers (figure 1). Cognitive
functioning was evaluated in 71 carriers (mean FSIQ=76.1;
SD=16.4; figure 2A) and was on average 32 points lower in de
novo carriers when compared to their non-carrier family
members (∼−2 SD, p=3.96×10−27; table 2A). There is a trend
towards higher FSIQ in de novo (n=32) versus inherited (n=14)
carriers (FSIQ 83 vs 74; p=0.13; table 2A and supplementary
table S1). Of note, parents of de novo deletion carriers who dir-
ectly enrol their child through a web based questionnaire (VIP
cohort) have a higher IQ than the mean of the general popula-
tion. Among carriers, 20% met DSM-IV-TR criteria for ID (65%
mild FSIQ 55–70 and 35% moderate FSIQ 40–55). There are no
differences in FSIQ between probands referred for neurodevelop-
mental disorders and carriers who were not medically ascertained
S1). Carriers’ verbal IQ (mean=74; SD=17.5; range 23–107;
n=42) is significantly lower than non-verbal IQ (mean=83.3;
SD=18.0; range 47–160; n=43) (p=0.02). Of the 24 carriers
evaluated in Europe, 20 (83%) had speech and language therapy
during childhood.
The 16p11.2 BP4-BP5 deletion has been repeatedly associated
with ASD, and is one of its most frequent known
aetiologies.4–8 Of the fully assessed carriers, ∼15% (8/55) of the
children and no adults met criteria for ASD by ADOS and
ADI-R. More than 70% (51/70) of non-ASD carriers were
found to have other DSM-IV-TR diagnoses27 including atten-
tion deficit and disruptive behaviour disorders, anxiety disor-
ders, mood disorders, and substance related disorders (table 2B).
There is a significant excess of males among carriers ascertained
for neurodevelopmental disorders (138 M/75 F; p=2.4×10−4) in
contrast to other criteria (table 1). Gender, however, is not a
significant covariate of FSIQ, adaptive level (Vineland), behav-
ioural scores (Social Responsiveness Scale, SRS), neurological
symptoms or any other trait (supplementary table S1).

Table 2 FSIQ (A), behavioural and psychiatric features (B) in deletion carriers and intrafamilial controls
Carriers
Probands Relatives Non-carriers
A Inherited De novo Unknown Parents Siblings Parents Siblings
Mean age (years) 14.7 10.9 15.7 36.8 10.2 38.6 11.7
Mean FSIQ 74 82.7 64.9 78.6 65.3 109.1 106.6
Number of cases 14 32* 14 7 4 46 22
B 16p11 Europe n (%)† Simons VIP n (%)† Total cohorts
DSM-IV-TR diagnosis Children Adults Children Adults n (%)
ASD‡ 1 (12.5) 0 7 (15) 0 8 (11.4)
Any DSM-IV-TR diagnosis other than ASD 4 (50)§ 6 (50)§ 39 (83) 2 (67) 51 (72.9)
No diagnosis 3 (37.5) 6 (50) 1 (2) 1 (33) 11 (15.7)
Total 8 12 47 3 70
*Two mosaic cases.
†10 probands and 10 relatives in the 16p11.2 European cohort and 44 probands and 6 relatives in Simons VIP.
‡ADOS and Autism Diagnostic Interview criteria
§Include attention deficit and disruptive behaviour disorders (n=4), anxiety disorders (n=5), mood disorders (n=3) and substance related disorders (n=2). Patients can have more than one
diagnosis.
ADOS, Autism Diagnostic Observation Schedule; ASD, autism spectrum disorder; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision; FSIQ, full scale
intelligence quotient.

J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203 663

 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com

Copy-number variation

We observed characteristic anthropometric patterns in
deletion carriers. Birth weight is below average (n=124, Z
score=−0.61; supplementary table S4), whereas Z scores for
BMI are significantly higher by the age of 3.5 (Z score=1.01,
p=0.03) (figure 3B). Longitudinal data show that this increase
in BMI can be sudden and dramatic (figure 3D, supplementary
figure S1). By the age of 7 years, obesity is a major comorbidity
present in more than 50% of the carriers (supplementary
figure S2). Excluding carriers ascertained for obesity, the fre-
quency reaches 75% in adults (36/48), and among all adult
obese patients 45% are morbidly obese (figure 2B). The variance
of BMI in deletion carriers is higher than in the general popula-
tion ( p=2.06×10−8). Hyperphagia was recorded (through par-
ental questionnaires or reports) in all carriers (n=14) with
obesity examined at the European site. The most severe cases
require strict control of food access through locked cupboards
and refrigerator.
BMI correlates neither with FSIQ (supplementary table S5)
nor behavioural or adaptive scores (SRS, VABS). Furthermore, it
is independent of ascertainment methods, inheritance,
gender, or the presence of neurological features (supplementary
table S1). Childhood obesity is, however, often associated with
accelerated prepubertal linear growth, although the mechanism
underlying this phenomenon remains unclear.36 In obese dele-
tion carriers, a similar association is observed (figure 3A) in
children whose height is increased (n=57, Z score=0.54,
p=6.8×10−4) and peaks at 9 years of age (Z score=1.08,
p=1.5×10−3). This is to be contrasted with short stature,
which is apparent in probands (n=182, Z score=-0.33,
p=3.2×10−3), newborns (n=88, Z score=−0.49, p=1.3×10−3),
non-obese children (n=91, Z score=−0.59, p=4.4×10−4), and
adults (n=32, Z score=−1.1, p=8.0×10−5) (figure 3A, supple-
mentary tables S1, S4, supplementary figure S3).
An overall increase in HC is observed in probands (n=146, Z
score=0.56, p=4.0×10−4) with macrocephaly (HC Z score ≥2)
present in 29/170 (17%) of the carriers. HC correlates positively
with BMI (r=0.45, p=2.8×10−8) (supplementary table S5) and
remains elevated after correcting for BMI, age, and gender (linear
model; mean corrected Z score=0.60, p=1.1×10−5). Obese dele-
tion carriers show an increased frequency of macrocephaly when
compared to non-obese carriers (32% and 10%, respectively;
p=1.8×10−3). Longitudinal data (figure 3B,C, supplementary
figure S4) show that HC, which is lower at birth by 0.57 Z scores
(n=58), increases during infancy (+1.74 Z scores, p=4.8×10−4),
several years before the elevation of BMI Z scores. In the Simon
Simplex Collection of ASD children, 41.3% of patients with
obesity have macrocephaly when compared to 12.5% in non-
obese patients (p=5.4×10−26) (supplementary figure S5).
Neurological features observed in patients referred for DD/ID
include a wide range of findings (supplementary table S2).
Gross motor delay was reported in 37.6% of the patients
(32/85 ascertained for DD/ID in the European cohorts), which
is consistent with previous series,10 23 37 and mean age of
walking is significantly delayed (mean=20.5 months, SD=8.6,
n=30, p=8.63×10−6). Epilepsy is a frequent feature reported in
47/195 (24%) of the probands. While this frequency is not sig-
nificantly different in non-medically ascertained carriers (5/38,
13%, p=0.2), it is higher in the fully assessed probands (22/54,
41%, p=1.6×10−2). A small fraction of carriers (12/233)
received a diagnosis of paroxysmal dyskinesia syndrome
(OMIM 128200). MRI performed in a subset of carriers (n=65)
showed mostly mild and non-recurrent features. Posterior fossa

Figure 3 Height, body mass index (BMI), and head circumference (HC) in 16p11.2 BP4-BP5 deletion carriers through development. Height
( panel A), BMI ( panel B) and HC ( panel C) mean Z scores (and corresponding p values in red) for each age window were computed using a mixed
effect model to analyse longitudinal and cross-sectional data together. p Values are derived from a two-sided t test of the fixed effects estimates
probing whether they are significantly different from 0. Full red dots are p values surviving multiple testing correction (significance’s threshold at
6.3×10−3 for height in both obese and non-obese, at 5.6×10−3 for BMI, and at 7.1×10−3 for HC) as opposed to empty red dots. Number of cases
N is indicated for each age category. Panel A: Deletion carriers were classified in two groups; either the ‘obese group’ (squares) if they presented
obesity at least once during their development, or the non-obese group (triangles). Height is significantly increased in prepubertal obese carriers
while non-obese children remain slightly shorter than the general population. Panel B: BMI is significantly elevated by 3.5 years of age. Panel C: HC
follows a rapid increase (+1.74 Z score, p=4.8×10−4) during infancy, and remains high throughout life. Panel D: Longitudinal measures of BMI in a
subset of 12 carriers illustrating different age onsets of BMI acceleration. The grey area specifies the interval between the 3rd and 97th centile as
defined by the WHO data (http://www.who.int/childgrowth/en) between 0–2 years and the Centre for Disease Control and Prevention data above
2 years of age. The white line marks the 50th centile. All available longitudinal data are included in supplementary figure S2.

664 J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203

 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com
and/or craniocervical junction related abnormalities (eg, Chiari
I malformation, cerebellar tonsillar ectopia, platybasia) were
present in 19 of 41 fully reviewed MRIs.
Malformations or major medical problems are present in
76/130 (58%) of the probands from both cohorts, of which 53
have only a single pathological feature (supplementary tables
S3 and S6). In non-medically ascertained carriers identified in
the families through cascade testing, this frequency is much
lower (10/38, 26.3%, p=7.6×10−4). No specific recurrent mal-
formation sequence or multisystemic involvement is observed
(supplementary table S6). There are, however, features likely to
be associated with the deletion which, in most cases, do not
require treatment such as vertebral abnormalities (hemiverteb-
rae or kyphoscoliosis affect ∼20% of carriers). Facial dys-
morphia was visible in 69/150 (46%) carriers, yet no recurrent
facial gestalt was observed in either cohort.
The frequency of this BP4-BP5 deletion (table 1) among
patients referred for clinical chromosome hybridisation micro-
array is similar for both consortia (0.28%). Though the two
cohorts were assembled in different continents and healthcare
systems, as well as using different ascertainment criteria, they
share striking similarities with the exception of the rate of
inherited cases. Among Simons VIP patients, the deletion arose
almost exclusively de novo (table 1). Globally, for participants
with available parental data (51%), the deletion occurred de
novo in 92/145 cases (including two mosaic cases) (64%) and
was inherited in the remaining cases (36%). Assuming a stable
prevalence of the deletion, this high rate of de novo events
implies decreased fitness of this deletion (0.52 and 0.20 in the
European and Simons VIP cohorts, respectively).
DISCUSSION
Our study demonstrates that the recurrent 600 kb BP4-BP5
deletion, which has a prevalence of ∼0.05% in the general
population,2 has a consistent impact on traits affecting adap-
tive skills. FSIQ is decreased by ∼2 SD in carriers of both
genders, about 20% of them meeting criteria for ID. Since the
FSIQ variance remains identical to that of the general popula-
tion ( p=0.25), approximately 30% of deletion carriers fall
within the normal range (FSIQ ≥85). Bias in these estimates is
unlikely since there were no differences in FSIQ scores of pro-
bands and non-medically ascertained carriers.
FSIQ does not capture the full range of disabilities experi-
enced by deletion carriers. A history of speech therapy is fre-
quent (83%) and psychiatric comorbidities affect >80% of
carriers. The penetrance of ASD is 15% in our cohorts
(table 2B), supporting the association of this deletion with
ASD.38 Increased growth velocity of HC during infancy recapi-
tulates the well documented pattern in idiopathic ASD. This
shared head growth pattern, which has attracted considerable
attention as a marker of abnormal brain development, has been
linked to an increase in white matter volume, brain weight and
numbers of neurones in the prefrontal cortex of ASD
patients.39
Obesity is a major comorbidity of 16p11.2 deletion carriers,
with a penetrance among adults of >70%. Durable weight loss
in adolescents or adults has not yet been documented: (1) two
adults treated by bariatric surgery relapsed several years later;
and (2) an adolescent dropped from 39.5 to 27.7 kg/m2 by
dieting and engaging in intense physical activity, but returned
to his initial weight 2 years after discontinuing this regimen.
Weight control is therefore recommended although no data are
available on the efficacy of early intervention in deletion car-
riers. The reported association of ID with obesity40 has led to
J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203
Copy-number variation
the proposal that impaired cognition may result in abnormal
eating behaviour and obesity.41 In 16p11.2 deletion carriers,
however, obesity occurs independently of cognitive function,
adaptive or social behaviour scores.
We hypothesise that the deletion directly affects the neural
circuitry involved in all these phenotypes, including energy
balance. The early increase in HC precedes the onset of obesity
(supplementary figure S4). This increase in HC is also observed
later in childhood and adolescence (figure 3C) when correlation
with brain volume is lower and contribution of skull thickness
higher.42 43 Furthermore we demonstrate that childhood
obesity in 16p11.2 deletion carriers, as well as in patients with
autism (SSC cohort), is a confounding factor contributing to
increased HC (supplementary figure S5). This deletion lowers
final adult height by 1 SD (supplementary figure S3), though
the well documented association between idiopathic childhood
obesity and prepubertal height acceleration36 is maintained in
obese children carrying the deletion (figure 3A,B, supplemen-
tary figure S3).
Epilepsy is the most frequent neurological disorder observed
in deletion carriers, and electroencephalogram (EEG) evaluation
should be prescribed if abnormal movements or behaviours sus-
picious for seizures are observed. A smaller and possibly under-
estimated fraction of carriers have paroxysmal dyskinesia
syndrome. We failed to observe a difference in the presence or
absence of epilepsy when stratifying for either cognitive func-
tioning, BMI or HC (supplementary table S1). It is possible
that epilepsy and the latter phenotypes are related to haploin-
sufficiency of distinct genes (figure 1B). Mutations in PRRT2, a
gene mapping to the deleted interval, were recently identified
in patients diagnosed with epilepsy and paroxysmal dyskin-
esia,44 whereas a 118kb deletion that encompasses MVP,
CDIPT, SEZ6L2, ASPHD1, and KCTD13 segregated in a three-
generation pedigree with ASD and other neurodevelopmental
abnormalities but not epilepsy.45 Of note, morpholino-driven
reduction of the expression level of the KCTD13 ortholog
resulted in macrocephaly in zebrafish, while its depletion in the
brain of mouse embryos resulted in an increase of proliferating
cells.35
Although we report a large spectrum of malformations (sup-
plementary table S3), the 16p11.2 deletion should not be
regarded primarily as a malformation syndrome. Indeed, the
majority of these abnormalities are infrequent, suggesting
either fortuitous associations or low penetrance (eg, coloboma/
microphthalmia) possibly through unmasking of recessive
mutations. Vertebral and spinal related anomalies (∼20%, sup-
plementary table S3) seem, however, to be strongly associated
with the deletion, suggesting that spine x-ray and orthopaedic
evaluations should be routinely performed in deletion carriers.
TBX6, which maps within the interval, is a candidate gene for
vertebral malformations since mice homozygous for a Tbx6
mutation showed rib and vertebral body anomalies.46
Additionally, TBX6 polymorphisms were associated with con-
genital scoliosis in the Han population.47
In conclusion, our study demonstrates in two independent
datasets that the 16p11.2 BP4-BP5 600 kb deletion consistently
and quantitatively impacts cognitive functioning, HC, BMI,
and growth. A range of behavioural disorders affects the vast
majority of carriers. Probands referred for neurodevelopmental
disorders or morbid obesity and carriers who were not medic-
ally ascertained (relatives of a proband) show similar values for
FSIQ and BMI, suggesting that ‘asymptomatic’ carriers are
uncommon. Five carriers within our cohorts presented an
FSIQ >100 and may therefore represent the higher end tail of
665
 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com
Copy-number variation
the FSIQ distribution of deletion carriers. All five presented lan-
guage disorders, autism, disruptive behaviour or obesity. The
deleterious impact of the deletion is further highlighted by its
low fitness reflected by the rarity of multigenerational carrier
families. In contrast to BMI, the variance of global cognitive
functioning (FSIQ) is the same among carriers and control
population, suggesting that the factors determining its variabil-
ity are identical to those at play in the general population and
unrelated to the 16p11.2 locus.
This comprehensive study of the 16p11.2 BP4-BP5 phenotype
helps to guide clinical monitoring and counselling of patients
and families and to potentially overcome the genetic counsel-
ling challenge posed by its variability. It illustrates that the
study of rare variants causing common diseases lacking pathog-
nomonic features requires the assembly and detailed clinical
characterisations of large cohorts, recruited using multiple
ascertainment criteria.
Author affiliations
1
Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland
2
Department of Neurology, University of California, San Francisco, California, USA
3
Department of Psychiatry, Boston Children’s Hospital, Harvard Medical School,
Boston, Massachusetts, USA
4
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
5
Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland
6
Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland
7
Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille,
France
8
Center for Integrative Brain Research, Children’s Research Institute, Seattle,
Washington, USA
9
Department of Child Psychiatry, SUPEA, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
10
Department of Psychiatry and Behavioral Science, University of Washington,
Seattle, Washington, USA
11
GHICL, Centre de Génétique Chromosomique, Hôpital Saint-Vincent de Paul, Lille,
France
12
Genomic Medicine Institute, Geisinger Clinic, Danville, Pennsylvania, USA
13
Department of Pediatrics, Psychology Section, Baylor College of Medicine, Houston,
Texas, USA
14
Department of Radiology, Boston Children’s Hospital, Harvard Medical School,
Boston, Massachusetts, USA
15
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
16
Department of Radiology, Baylor College of Medicine, Houston, Texas, USA
17
Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland
18
Department of Human Genetics, Emory University, Atlanta, Georgia, USA
19
Department of Radiology and Biomedical Imaging, University of California,
San Francisco, San Francisco, California, USA
20
Department of Pediatrics, Section of Pediatric Neurology and Developmental
Neuroscience, Baylor College of Medicine, Houston, Texas, USA
21
Department of Neurology, Boston Children’s Hospital, Harvard Medical School,
Boston, Massachusetts, USA
22
Department of Neurology, Seattle Children’s Research Institute & University of
Washington, Seattle, Washington, USA
23
Simons Foundation, New York, New York, USA
24
Departments of Pediatrics and Medicine, Columbia University, New York, New York,
USA
*Members of the consortia are listed in the Supplemental Appendix.
Acknowledgements We thank the participants, families, and referring providers for
their contribution. SJ is recipient of a ‘bourse de relève académique de la Faculté de
Biologie et Médecine de l’Université de Lausanne’ and KM is a grantee of a
scholarship from the Swiss Scientific Exchange NMS Programme. This work is
supported by the Leenaards Foundation Prize (SJ and AR), the Swiss National
Science Foundation (AR and JSB) and a specific SNSF Sinergia grant (AR).
Phenotyping of EGC UT individuals was supported by Targeted Financing from
Estonian Government grant SF0180142Cs08, Centre of Translational Genomics grant
SP1GVARENG, and by the European Union through the European Regional
Development Fund, in the frame of Centre of Excellence in Genomics. The Simons
VIP work is supported by the Simons Foundation Autism Research Initiative (SFARI).
We thank the coordinators and staff at the Simons Simplex Collection (SSC) sites.
We are grateful to all of the families at the participating Simons Simplex Collection
666
(SSC) sites, as well as the principal investigators (A Beaudet, R Bernier,
J Constantino, E Cook, E Fombonne, D Geschwind, R Goin-Kochel, E Hanson, D Grice,
A Klin, D Ledbetter, C Lord, C Martin, D Martin, R Maxim, J Miles, O Ousley,
K Pelphrey, B Peterson, J Piggot, C Saulnier, M State, W Stone, J Sutcliffe, C Walsh,
Z Warren, E Wijsman). We appreciate obtaining access to phenotypic data on SFARI
Base. Approved researchers can obtain the SSC population dataset described in this
study by applying at https://base.sfari.org
Collaborators List of contributors to the 16p11.2 European Consortium: Marie
Claude Addor; Benoit Arveiler; Marco Belfiore; Frédérique Bena; Laura Bernardini;
Patricia Blanchet; Dominique Bonneau; Odile Boute; Patrick Callier; Dominique
Campion; Jean Chiesa; Marie Pierre Cordier; Jean Marie Cuisset; Albert David; Nicole
de Leeuw; Bert de Vries; Gérard Didelot; Martine Doco-Fenzy; Bénédicte Duban
Bedu; Christèle Dubourg; Sophie Dupuis-Girod; Christina R. Fagerberg; Laurence
Faivre; Florence Fellmann; Bridget A. Fernandez; Richard Fisher; Elisabeth Flori; Alice
Goldenberg; Delphine Heron; Muriel Holder; Juliane Hoyer; Bertrand Isidor; Sylvie
Jaillard; Philippe Jonveaux; Sylvie Joriot; Hubert Journel; Frank Kooy; Cédric le
Caignec; Bruno Leheup; Marie-Pierre Lemaitre; Suzanne Lewis; Valérie Malan;
Michèle Mathieu-Dramard; Andres Metspalu; Fanny Morice-Picard; Mafalda Mucciolo;
Eve Oiglane-Shlik; Katrin Ounap; Laurent Pasquier; Florence Petit; Anne Philippe;
Ghislaine Plessis; Fabienne Prieur; Jacques Puechberty; Evica Rajcan-Separovic; Anita
Rauch; Alessandra Renieri; Claudine Rieubland; Caroline Rooryck; Katharina
Magdalena Rötzer; Mariken Ruiter; Damien Sanlaville; Stéphanie Selmoni; Yiping
Shen; Vanessa Siffredi; Jacques Thonney; Louis Vallée; Ellen van Binsbergen; Nathalie
Van der Aa; Mieke M. van Haelst; Jacqueline Vigneron; Catherine Vincent-Delorme;
Disciglio Vittoria; Anneke T Vulto-van Silfhout; Robert M Witwicki; Simon
A. Zwolinski. List of contributors of the Simons VIP Consortium: Alexandra Bowe;
Arthur L Beaudet; Christie M Brewton; Zili Chu; Allison G Dempsey; Yolanda L Evans;
Silvia Garza; Stephen M Kanne; Anna L Laakman; Morgan W Lasala; Ashlie V
Llorens; Gabriela Marzano; Timothy J Moss; Kerri P Nowell; Monica B Proud; Qixuan
Chen; Roger Vaughan; Jeffrey Berman; Lisa Blaskey; Katherine Hines; Sudha Kessler;
Sarah Y Khan; Saba Qasmieh; Audrey Lynn Bibb; Andrea M Paal; Patricia Z Page;
Bethanny Smith-Packard; Randy Buckner; Jordan Burko; Alyss Lian Cavanagh; Bettina
Cerban; Anne V Snow; LeeAnne Green Snyder; Rebecca McNally Keehn; David T
Miller; Fiona K Miller; Jennifer Endre Olson; Christina Triantafallou; Nicole Visyak;
Constance Atwell; Marta Benedetti; Gerald D Fischbach; Marion Greenup; Alan
Packer; Polina Bukshpun; Maxwell Cheong; Corby Dale; Sarah E Gobuty; Leighton
Hinkley; Rita J Jeremy; Hana Lee; Tracy L Luks; Elysa J Marco; Alastair J Martin;
Kathleen E McGovern; Srikantan S Nagarajan; Julia Owen; Brianna M Paul; Nicholas
J Pojman; Tuhin Sinha; Vivek Swarnakar; Mari Wakahiro; Hanalore Alupay; Benjamin
Aaronson; Sean Ackerman; Katy Ankenman; Jenna Elgin; Jennifer Gerdts; Kelly
Johnson; Beau Reilly; Dennis Shaw; Arianne Stevens; Tracey Ward; Julia Wenegrat;
Timothy PL Roberts
Contributors All authors contributed to the concept, design, acquisition of data or
analysis and interpretation of data. All authors contributed to drafting or revising the
content and approved the final version.
Competing interests Competing interests are disclosed in the ICMJE conflit of
interest forms.
Ethics approval This study was approved by the IRB of the University of Lausanne,
the IRB of the Simons Foundation as well as the IRB of each site conducting the
study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data on the Simons VIP subjects are available through
SFARI Base at https://sfari.org/resources/sfari-base.
REFERENCES
1. Walters RG, Jacquemont S, Valsesia A, de Smith AJ, Martinet D, Andersson J,
Falchi M, Chen F, Andrieux J, Lobbens S, Delobel B, Stutzmann F, El-Sayed Moustafa
JS, Chevre JC, Lecoeur C, Vatin V, Bouquillon S, Buxton JL, Boute O,
Holder-Espinasse M, Cuisset JM, Lemaitre MP, Ambresin AE, Brioschi A, Gaillard M,
Giusti V, Fellmann F, Ferrarini A, Hadjikhani N, Campion D, Guilmatre A, Goldenberg
A, Calmels N, Mandel JL, Le Caignec C, David A, Isidor B, Cordier MP, Dupuis-Girod
S, Labalme A, Sanlaville D, Beri-Dexheimer M, Jonveaux P, Leheup B, Ounap K,
Bochukova EG, Henning E, Keogh J, Ellis RJ, Macdermot KD, van Haelst MM,
Vincent-Delorme C, Plessis G, Touraine R, Philippe A, Malan V, Mathieu-Dramard M,
Chiesa J, Blaumeiser B, Kooy RF, Caiazzo R, Pigeyre M, Balkau B, Sladek R,
Bergmann S, Mooser V, Waterworth D, Reymond A, Vollenweider P, Waeber G, Kurg
A, Palta P, Esko T, Metspalu A, Nelis M, Elliott P, Hartikainen AL, McCarthy MI,
Peltonen L, Carlsson L, Jacobson P, Sjostrom L, Huang N, Hurles ME, O’Rahilly S,
Farooqi IS, Mannik K, Jarvelin MR, Pattou F, Meyre D, Walley AJ, Coin LJ, Blakemore
AI, Froguel P, Beckmann JS. A new highly penetrant form of obesity due to
deletions on chromosome 16p11.2. Nature 2010;463:671–5.
2. Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z,
Martinet D, Shen Y, Valsesia A, Beckmann ND, Thorleifsson G, Belfiore M, Bouquillon
J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203
 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com
S, Campion D, de Leeuw N, de Vries BB, Esko T, Fernandez BA, Fernandez-Aranda F,
Fernandez-Real JM, Gratacos M, Guilmatre A, Hoyer J, Jarvelin MR, Kooy RF, Kurg
A, Le Caignec C, Mannik K, Platt OS, Sanlaville D, Van Haelst MM, Villatoro Gomez
S, Walha F, Wu BL, Yu Y, Aboura A, Addor MC, Alembik Y, Antonarakis SE, Arveiler
B, Barth M, Bednarek N, Bena F, Bergmann S, Beri M, Bernardini L, Blaumeiser B,
Bonneau D, Bottani A, Boute O, Brunner HG, Cailley D, Callier P, Chiesa J, Chrast J,
Coin L, Coutton C, Cuisset JM, Cuvellier JC, David A, de Freminville B, Delobel B,
Delrue MA, Demeer B, Descamps D, Didelot G, Dieterich K, Disciglio V, Doco-Fenzy
M, Drunat S, Duban-Bedu B, Dubourg C, El-Sayed Moustafa JS, Elliott P, Faas BH,
Faivre L, Faudet A, Fellmann F, Ferrarini A, Fisher R, Flori E, Forer L, Gaillard D,
Gerard M, Gieger C, Gimelli S, Gimelli G, Grabe HJ, Guichet A, Guillin O, Hartikainen
AL, Heron D, Hippolyte L, Holder M, Homuth G, Isidor B, Jaillard S, Jaros Z,
Jimenez-Murcia S, Helas GJ, Jonveaux P, Kaksonen S, Keren B, Kloss-Brandstatter
A, Knoers NV, Koolen DA, Kroisel PM, Kronenberg F, Labalme A, Landais E, Lapi E,
Layet V, Legallic S, Leheup B, Leube B, Lewis S, Lucas J, MacDermot KD,
Magnusson P, Marshall C, Mathieu-Dramard M, McCarthy MI, Meitinger T,
Mencarelli MA, Merla G, Moerman A, Mooser V, Morice-Picard F, Mucciolo M,
Nauck M, Ndiaye NC, Nordgren A, Pasquier L, Petit F, Pfundt R, Plessis G,
Rajcan-Separovic E, Ramelli GP, Rauch A, Ravazzolo R, Reis A, Renieri A, Richart C,
Ried JS, Rieubland C, Roberts W, Roetzer KM, Rooryck C, Rossi M, Saemundsen E,
Satre V, Schurmann C, Sigurdsson E, Stavropoulos DJ, Stefansson H, Tengstrom C,
Thorsteinsdottir U, Tinahones FJ, Touraine R, Vallee L, van Binsbergen E, Van der Aa
N, Vincent-Delorme C, Visvikis-Siest S, Vollenweider P, Volzke H, Vulto-van Silfhout
AT, Waeber G, Wallgren-Pettersson C, Witwicki RM, Zwolinksi S, Andrieux J, Estivill
X, Gusella JF, Gustafsson O, Metspalu A, Scherer SW, Stefansson K, Blakemore AI,
Beckmann JS, Froguel P. Mirror extreme BMI phenotypes associated with gene
dosage at the chromosome 16p11.2 locus. Nature 2011;478:97–102.
3. Walsh KM, Bracken MB. Copy number variation in the dosage-sensitive 16p11.2
interval accounts for only a small proportion of autism incidence: a systematic
review and meta-analysis. Genet Med: Off J Am Coll Med Genet 2011;13:377–84.
4. Kumar RA, KaraMohamed S, Sudi J, Conrad DF, Brune C, Badner JA, Gilliam TC,
Nowak NJ, Cook EH Jr, Dobyns WB, Christian SL. Recurrent 16p11.2 microdeletions
in autism. Hum Mol Genet 2008;17:628–38.
5. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner
R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J,
Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A,
Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V,
Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P,
Scherer SW. Structural variation of chromosomes in autism spectrum disorder. Am
J Hum Genet 2008;82:477–88.
6. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon
S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee
AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS,
Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam
TC, Ye K, Wigler M. Strong association of de novo copy number mutations with
autism. Science 2007;316:445–9.
7. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E,
Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D,
Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL,
Daly MJ. Association between microdeletion and microduplication at 16p11.2 and
autism. N Engl J Med 2008;358:667–75.
8. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu
SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB,
Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM,
Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS,
Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch
JD, O’Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu
TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Gunel M, Lifton RP,
Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM,
Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr,
Geschwind D, Roeder K, Devlin B, State MW. Multiple recurrent de novo CNVs,
including duplications of the 7q11.23 Williams syndrome region, are strongly
associated with autism. Neuron 2011;70:863–85.
9. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S,
Hamilton-Shield J, Clayton-Smith J, O’Rahilly S, Hurles ME, Farooqi IS. Large, rare
chromosomal deletions associated with severe early-onset obesity. Nature
2010;463:666–70.
10. Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, Scott DA, Probst FJ, Craigen
WJ, Graham BH, Pursley A, Clark G, Lee J, Proud M, Stocco A, Rodriguez DL, Kozel
BA, Sparagana S, Roeder ER, McGrew SG, Kurczynski TW, Allison LJ, Amato S,
Savage S, Patel A, Stankiewicz P, Beaudet AL, Cheung SW, Lupski JR. Recurrent
reciprocal 16p11.2 rearrangements associated with global developmental delay,
behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet
2010;47:332–41.
11. Schaaf CP, Goin-Kochel RP, Nowell KP, Hunter JV, Aleck KA, Cox S, Patel A, Bacino
CA, Shinawi M. Expanding the clinical spectrum of the 16p11.2 chromosomal
rearrangements: three patients with syringomyelia. Eur J Hum Genet: EJHG
2011;19:152–6.
J Med Genet 2012;49:660–668. doi:10.1136/jmedgenet-2012-101203
Copy-number variation
12. Dale RC, Grattan-Smith P, Fung VS, Peters GB. Infantile convulsions and
paroxysmal kinesigenic dyskinesia with 16p11.2 microdeletion. Neurology
2011;77:1401–2.
13. Puvabanditsin S, Nagar MS, Joshi M, Lambert G, Garrow E, Brandsma E.
Microdeletion of 16p11.2 associated with endocardial fibroelastosis. Am J Med
Genet A 2010;152A:2383–6.
14. Bardakjian TM, Kwok S, Slavotinek AM, Schneider AS. Clinical report of
microphthalmia and optic nerve coloboma associated with a de novo microdeletion
of chromosome 16p11.2. Am J Med Genet A 2010;152A:3120–3.
15. Bijlsma EK, Gijsbers AC, Schuurs-Hoeijmakers JH, van Haeringen A, Fransen van
de Putte DE, Anderlid BM, Lundin J, Lapunzina P, Perez Jurado LA, Delle Chiaie B,
Loeys B, Menten B, Oostra A, Verhelst H, Amor DJ, Bruno DL, van Essen AJ,
Hordijk R, Sikkema-Raddatz B, Verbruggen KT, Jongmans MC, Pfundt R, Reeser HM,
Breuning MH, Ruivenkamp CA. Extending the phenotype of recurrent rearrangements
of 16p11.2: deletions in mentally retarded patients without autism and in normal
individuals. Eur J Med Genet 2009;52:77–87.
16. Fernandez BA, Roberts W, Chung B, Weksberg R, Meyn S, Szatmari P,
Joseph-George AM, Mackay S, Whitten K, Noble B, Vardy C, Crosbie V, Luscombe
S, Tucker E, Turner L, Marshall CR, Scherer SW. Phenotypic spectrum associated
with de novo and inherited deletions and duplications at 16p11.2 in individuals
ascertained for diagnosis of autism spectrum disorder. J Med Genet
2010;47:195–203.
17. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church
DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh
A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM,
Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland
EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. Consensus
statement: chromosomal microarray is a first-tier clinical diagnostic test for
individuals with developmental disabilities or congenital anomalies. Am J Hum Genet
2010;86:749–64.
18. The Simons Vip C. Simons Variation in Individuals Project (Simons VIP): a
genetics-first approach to studying autism spectrum and related neurodevelopmental
disorders. Neuron 2012;73:1063–7.
19. Ghebranious N, Giampietro PF, Wesbrook FP, Rezkalla SH. A novel microdeletion at
16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and
mild mental retardation. Am J Med Genet A 2007;143A:1462–71.
20. Shiow LR, Paris K, Akana MC, Cyster JG, Sorensen RU, Puck JM. Severe
combined immunodeficiency (SCID) and attention deficit hyperactivity disorder
(ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2
deletion. Clin Immunol 2009;131:24–30.
21. Shimojima K, Inoue T, Fujii Y, Ohno K, Yamamoto T. A familial 593-kb microdeletion
of 16p11.2 associated with mental retardation and hemivertebrae. Eur J Med Genet
2009;52:433–5.
22. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO,
Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra
D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P,
Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S,
Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimaki T, Puura
K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem
L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nothen
MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe
JS, Skuse D, Gill M, Gallagher L, Mendell NR, Craddock N, Owen MJ, O’Donovan
MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL,
King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia.
Nat Genet 2009;41:1223–7.
23. Hanson E, Nasir RH, Fong A, Lian A, Hundley R, Shen Y, Wu BL, Holm IA, Miller
DT. Cognitive and behavioral characterization of 16p11.2 deletion syndrome. J Dev
Behav Pediatr: JDBP 2010;31:649–57.
24. Fischbach GD, Lord C. The Simons Simplex Collection: a resource for identification
of autism genetic risk factors. Neuron 2010;68:192–5.
25. Wechsler D. Wechsler adult intelligence scale—third edition. Administration and
scoring manual San Antonio, TX: The Psychological Corporation, 1997.
26. Sparrow SS, Cichetti DV, Balla DA. Vineland adaptative behavior scales. 2nd edn.
Livonia, MN: Pearson Assessments, 2006.
27. APA. Diagnostic and statistical manual of mental disorders, DSM-IV-TR. Washington,
DC: American Psychiatric Association, 2000.
28. Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised
version of a diagnostic interview for caregivers of individuals with possible pervasive
developmental disorders. J Autism Dev Disord 1994;24:659–85.
29. Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, Pickles A,
Rutter M. The autism diagnostic observation schedule-generic: a standard measure
of social and communication deficits associated with the spectrum of autism. J
Autism Dev Disord 2000;30:205–23.
30. Preisig M, Fenton BT, Matthey ML, Berney A, Ferrero F. Diagnostic interview for
genetic studies (DIGS): inter-rater and test-retest reliability of the French version. Eur
Arch Psychiatry Clin Neurosci 1999;249:174–9.
31. Wardle J, Guthrie CA, Sanderson S, Rapoport L. Development of the Children’s
Eating Behaviour Questionnaire. J Child Psychol Psychiatry 2001;42:963–70.
667
 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com

Copy-number variation

32. Achenbach TM. Manual for the child behavior checklist and the revised child
behavior profile. 2nd edn. Burlington: University of Vermont, Department of
Psychiatry, 1991.
33. Constantino JN, Gruber CP. Social Responsiveness Scale (SRS). Los Angeles, CA:
Western Psychological Services, 2005.
34. Gao X, Starmer J, Martin ER. A multiple testing correction method for genetic
association studies using correlated single nucleotide polymorphisms. Genet
Epidemiol 2008;32:361–9.
35. Golzio C, Willer J, Talkowski ME, Oh EC, Taniguchi Y, Jacquemont S, Reymond A,
Sun M, Sawa A, Gusella JF, Kamiya A, Beckmann JS, Katsanis N. KCTD13 is a
major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number
variant. Nature 2012;485:363–7.
36. Martinelli CE, Keogh JM, Greenfield JR, Henning E, van der Klaauw AA,
Blackwood A, O’Rahilly S, Roelfsema F, Camacho-Hubner C, Pijl H, Farooqi IS.
Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with
increased linear growth and final height, fasting hyperinsulinemia, and
incompletely suppressed growth hormone secretion. J Clin Endocrinol Metab
2011;96:E181–8.
37. Rosenfeld JA, Coppinger J, Bejjani BA, Girirajan S, Eichler EE, Shaffer LG, Ballif BC.
Speech delays and behavioral problems are the predominant features in individuals
with developmental delays and 16p11.2 microdeletions and microduplications.
J Neurodev Disord 2010;2:26–38.
38. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B,
Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M.
Rare de novo and transmitted copy-number variation in autistic spectrum disorders.
Neuron 2011;70:886–97.
39. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet
MJ, Barnes CC, Pierce K. Neuron number and size in prefrontal cortex of children
with autism. JAMA: J Am Med Assoc 2011;306:2001–10.
40. Melville CA, Hamilton S, Hankey CR, Miller S, Boyle S. The prevalence and
determinants of obesity in adults with intellectual disabilities. Obes Rev
2007;8:223–30.
41. Galioto R, Spitznagel MB, Strain G, Devlin M, Cohen R, Paul R, Crosby RD, Mitchell
JE, Gunstad J. Cognitive function in morbidly obese individuals with and without
binge eating disorder. Compr Psychiatry 2012;53:490–5.
42. Brain Development Cooperative G. Total and regional brain volumes in a
population-based normative sample from 4 to 18 years: the NIH MRI Study of
Normal Brain Development. Cereb Cortex 2012;22:1–12.
43. Bartholomeusz HH, Courchesne E, Karns CM. Relationship between head
circumference and brain volume in healthy normal toddlers, children, and adults.
Neuropediatrics 2002;33:239–41.
44. Chen WJ, Lin Y, Xiong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang
QJ, Li HF, Murong SX, Xu J, Wang N, Wu ZY. Exome sequencing identifies
truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat
Genet 2011;43:1252–5.
45. Crepel A, Steyaert J, De la Marche W, De Wolf V, Fryns JP, Noens I, Devriendt K,
Peeters H. Narrowing the critical deletion region for autism spectrum disorders on
16p11.2. Am J Med Genet B, Neuropsychiatric Genet: Off Publication Int Soc
Psychiatric Genet 2011;156:243–5.
46. Watabe-Rudolph M, Schlautmann N, Papaioannou VE, Gossler A. The mouse
rib-vertebrae mutation is a hypomorphic Tbx6 allele. Mech Dev 2002;
119:251–6.
47. Fei Q, Wu Z, Wang H, Zhou X, Wang N, Ding Y, Wang Y, Qiu G.
The association analysis of TBX6 polymorphism with susceptibility to
congenital scoliosis in a Chinese Han population. Spine (Phila Pa 1976)
2010;35:983–8.
48. Zhang F, Gu W, Hurles ME, Lupski JR. Copy number variation in human health,
disease, and evolution. Annu Rev Genomics Hum Genet 2009;10:451–81.
49. Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S,
Bader PI, Hamati A, Reitnauer PJ, Smith R, Stockton DW, Muhle H, Helbig I,
Eichler EE, Ballif BC, Rosenfeld J, Tsuchiya KD. Recurrent 200-kb
deletions of 16p11.2 that include the SH2B1 gene are associated with
developmental delay and obesity. Genet Med: Off J Am Coll Med Genet
2010;12:641–7.

Miscellaneous
Corrections
10.1136/jmedgenet-2012-101175corr1
Lill CM, Liu T, Schjeide BM, Roehr JT, Akkad DA, Damotte V, Alcina A, Ortiz MA, Arroyo R, Lopez de Lapuente A, Blaschke P,
Winkelmann A, Gerdes LA, Luessi F, Fernandez O, Izquierdo G, Antigüedad A, Hoffjan S, Cournu-Rebeix I, Gromöller S, Faber
H, Liebsch M, Meissner E, Chanvillard C, Touze E, Pico F, Corcia P; ANZgene Consortium, Dörner T, Steinhagen-Thiessen E,
Bäckman L, Heekeren HR, Li SC, Lindenberger U, Chan A, Hartung HP, Aktas O, Lohse P, Kümpfel T, Kubisch C, Epplen JT,
Zettl UK, Fontaine B, Vandenbroeck K, Matesanz F, Urcelay E, Bertram L, Zipp F Closing the case of APOE in multiple sclerosis:
no association with disease risk in over 29 000 subjects. J Med Genet 2012;49:558–62 doi:10.1136/jmedgenet-2012-101175. Some
of the author affiliations were incorrectly list. A data supplement of the PDF shows the correct affiliations.

10.1136/jmedgenet-2012-101159corr1
Fassone E, Rahman S. Complex I deficiency: clinical features, biochemistry and molecular genetics. J Med Genet. 2012;49:578–90.
In the above article updated figures were not included in the proof. These will be uploaded with the article as a data supplement.

668 J Med Genet October 2012 Vol 49 No 10

 Downloaded from jmg.bmj.com on January 31, 2013 - Published by group.bmj.com

A 600 kb deletion syndrome at 16p11.2 leads

to energy imbalance and neuropsychiatric
disorders
Flore Zufferey, Elliott H Sherr, Noam D Beckmann, et al.

J Med Genet 2012 49: 660-668

doi: 10.1136/jmedgenet-2012-101203

Updated information and services can be found at:

http://jmg.bmj.com/content/49/10/660.full.html

These include:
Data Supplement "Supplementary Data"
http://jmg.bmj.com/content/suppl/2012/11/11/jmedgenet-2012-101203.DC1.html

References This article cites 44 articles, 7 of which can be accessed free at:
http://jmg.bmj.com/content/49/10/660.full.html#ref-list-1

Open Access This is an open-access article distributed under the terms of the
Creative Commons Attribution Non-commercial License, which permits
use, distribution, and reproduction in any medium, provided the original
work is properly cited, the use is non commercial and is otherwise in
compliance with the license. See:
http://creativecommons.org/licenses/by-nc/3.0/ and
http://creativecommons.org/licenses/by-nc/3.0/legalcode
Email alerting Receive free email alerts when new articles cite this article. Sign up in
service the box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections
Open access (71 articles)
Obesity (nutrition) (50 articles)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/